Oral epithelium cancer is a common malignancy that affects 40,000 new patients in the United States each year. Mortality from this disease remains high because of the development of distant metastases and the emergence of therapy-resistant local and regional recurrences. The median age at diagnosis for head and neck squamous cell carcinoma (HNSCC) has classically and historically been set at 60 years. The incidence of a subset of neoplasms originating from the oral cavity and the oropharynx, however, in young adults, age <40, has been steadily and rapidly increasing. Furthermore, carcinoma of the tongue appears to account for the majority of this increase in incidence and has now become the second most common malignancy in the oral cavity. Recent research suggests that tumor formation may result from the development of cancer stem cells. According to this hypothesis tumors harbor a small population of cancer stem cells (CSC) that are responsible for re-growth of a tumor following unsuccessful treatment and for the establishment of metastases. The successful treatment to eliminate cancer need to take into account the unusual properties of the CSC subpopulation. A major problem to the development of such a treatment strategy is that methods are still lacking that can readily distinguish CSCs from their differentiating progeny and from their normal tissue counterparts. Purification of cancer stem cells from human tumors is limited by patient heterogeneity and availability of fresh and sizable tumor samples. Moreover, current markers enrich for but do not allow complete purification of human CSCs. Based on our preliminary observations we propose an alternative route to obtain and characterize oral epithelia normal and cancer stem cells using mouse model. Obtained in our study gene expression profiles of normal tongue epithelium stem cells versus cancer stem cells could be used to identify cell surface or secreted proteins enriched in CSC population, which may be used to guide the identification, further purification, and blood-based detection of human cancer. Experimentally isolated CSC may also be used for drug screening to identify compounds that specifically target cancer stem cells. Further, a key goal in cancer research is to identify the mechanism by which cancer stem cells arise and self- renew. Mouse models with defined CSC offer the possibility of dissecting the temporal and functional dynamics of these processes. PUBLIC HEALTH RELEVANCE: Oral epithelium cancer is a common malignancy with still high mortality rate. Recent studies suggest that tumors harbor a small population of cancer stem cells (CSC) that are responsible for re-growth of a tumor following unsuccessful treatment. To improve the current treatment we need to take into account the unusual properties of the CSC subpopulation. Our overall goal is to isolate and characterize normal and cancer tongue epithelium stem cells and characterize how the tongue epithelium cancer stem cells differ from their differentiating progeny and from normal stem cells. This might allow to target selectively and eliminate CSC, thus improving therapeutic outcome.